CASE REPORT
Vismodegib dose reduction effective when
combined with itraconazole for the treatment
of advanced basal cell carcinoma
Jaeyoung Yoon, MD, PhD
Wentzville, Missouri
Key words: advanced basal cell carcinoma; hedgehog inhibitor; itraconazole; vismodegib.
INTRODUCTION
Basal cell carcinoma (BCC) is the most common
cancer in the United States with an incidence of 3-4
million per year.1 Most cases are easily treated with
high cure rates using surgical methods such as wide
excision, electrodessication and curettage or Mohs
micrographic surgery, and, less commonly, radiation
therapy. However, advanced and metastatic BCCs
are more difficult to treat. Two oral medications,
vismodegib and sonidegib, have recently become an
option for these patients. They work by inhibiting
the intracellular hedgehog (Hh) pathway. The link
between the defect of this signaling mechanism and
formation of BCC was initially shown in patients with
Gorlin Syndrome.2 Vismodegib clinical trial data
have shown a response rate close to 60%.3
Limitations of vismodegib are the side effects
experienced by most patients. Over half of the
patients have mild-to-moderate adverse events, and
21.2% of the patients discontinued therapy due to
this in the international, multicenter, single arm,
phase II ERIVANCE BCC clinical trial by
Genentech.4 The most common side effects are
muscle spasm, fatigue, alopecia, dysgeusia, and
weight loss.
Itraconazole is a relatively safe drug, which has
long been used as an antifungal agent. Recently, it
has also shown inhibitory effects on the Hh
pathway.5 The use of oral itraconazole at doses of
200-400 mg/day showed a significant reduction of
BCC size in some patients in an exploratory trial.6
There is some speculation that using Hh pathway
inhibitors together may work better than single
dosing.7,8 The binding sites on the smoothened
From the Yoon Dermatology, Wentzville, Missouri.
Funding sources: None.
Conflicts of interest: Dr Yoon has filed a patent on the combina-
tion use of hedgehog inhibitors for cancer treatment.
IRB approval status: Not applicable.
Correspondence to: Jaeyoung Yoon, MD, PhD, Yoon Dermatology,
1060 Meyer Road, Wentzville, MO 63385. E-mail: jaeyoung99@
gmail.com.
Abbreviations used:
BCC: basal cell carcinoma
Hh: hedgehog
protein of both of these Hh inhibitors appear to be
at different locations.9 In addition, molecular simu-
lation models show that the binding of one does not
interfere with the binding of the other, suggesting
that both may work together as antagonists.10 There
are multiple examples in medicine where combining
drugs regimens can improve clinical outcome,
notably in HIV therapy and cancer chemotherapy.
This case report describes two patients who were
treated with reduced doses of both vismodegib and
itraconazole for locally advanced BCCs.
CASE DESCRIPTION
Case 1
An 84-year-old man was seen in the clinic for a
BCC of the left chin (Fig 1, A), which recurred 2 years
after Mohs micrographic surgery. He presented with
a large, fixed, ulcerated, firm tumor. Magnetic
resonance imaging showed the tumor approxi-
mating the bone. He refused surgery given his age
and the possibility of an extensive surgical interven-
tion. He was administered vismodegib 150 mg once
per week and itraconazole 200 mg/day.
Notable clinical improvement was observed after
4 weeks of treatment (Fig 1, B). After 12 weeks, the
area was completely healed, and the tissue was more
supple (Fig 1, C ). He continued the medications for a
total of 28 weeks. His last follow-up was 16 months
JAAD Case Reports 2021;7:107-9.
2352-5126
Ó 2020 by the American Academy of Dermatology, Inc. Published
by Elsevier, Inc. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).
https://doi.org/10.1016/j.jdcr.2020.11.014
107
108 Yoon JAAD CASE REPORTS
JANUARY 2021

Fig 1. Deep recurrent BCC on the left chin treated with combination therapy. A, Pre-treatment.
B, 4 weeks of treatment. C, 12 weeks of treatment. D, 16 months after the initiation of therapy.
BCC, Basal cell carcinoma.

after the initiation of treatment, and there was no

clinical evidence of tumor progression (Fig 1, D).
This patient experienced body hair loss and
muscle spasms of the legs, which were described
as mild and tolerable. There were no laboratory
abnormalities throughout the treatment.

Case 2
An 85-year-old man presented for Mohs micro-
graphic surgery for a large BCC on his right ear
(Fig 2, A). He was concerned about the risk
of deformity and asked for an alternative treatment.
He was placed on vismodegib 150 mg twice a
week (Mondays and Fridays) and itraconazole
100 mg/day.
There was significant clinical improvement after
8 weeks of treatment (Fig 2, B). At 16 weeks, the ear
was healed (Fig 2, C ). The total treatment duration
was 21 weeks. At his last follow-up at 16 months after
the initiation of the combination therapy, no clinical
evidence of tumor regrowth was observed (Fig 2, D).

DISCUSSION
The recommended dosing for vismodegib is
150 mg/day. Pharmacokinetic studies support this
daily regimen for optimal blood concentration.11 In
both patients presented here, a significantly lower
Fig 2. Advanced BCC on the right ear treated with
combination therapy. A, Pre-treatment. B, 8 weeks of
treatment. C, 16 weeks of treatment. D, 16 months after the
initiation of therapy. BCC, Basal cell carcinoma.
JAAD CASE REPORTS
VOLUME 7
dose of vismodegib was used, along with a low dose
of itraconazole, compared with the exploratory trial
mentioned above. In case 1, one seventh of the
recommended dose was given along with itracona-
zole 200 mg/day. And in case 2, two seventh of the
recommended dose was used with itraconazole
100 mg/day. In both cases, the patients showed
clearance by week 16. This suggests that combining
these two agents have at least an additive effect in
some patients.
Patients were monitored carefully while on com-
bination therapy. They were seen in the clinic on a
monthly basis, and bloodwork was performed at
each visit. Laboratory tests included a complete
metabolic panel, a complete blood count, a hepatic
panel, and total creatinine kinase. There were no
laboratory abnormalities throughout the duration of
treatment in either patient. The patient in case 1
experienced mild muscle cramps and loss of body
hair. The patient in case 2 denied any adverse effects
at all. In contrast, patients who receive daily vismo-
degib dosed at 150 mg/day almost always experi-
ence multiple and/or moderate side effects.4 Using
vismodegib at a reduced dose with milder side
effects could make oral Hh pathway inhibtion
treatment more tolerable, especially for those who
need long-term therapy.
It is possible that vismodegib or itraconazole
alone resulted in the clinical effects observed here,
although such low doses of each drug alone have not
been previously reported to be as effective. It is also
possible one of these drugs causes an elevated serum
level of the other when used together, as they are
metabolized by similar pathways through the liver.
Itraconazole is an inhibitor of the cytochrome P-450
pathway12 and can elevate the blood concentration
of vismodegib. Measuring serum levels of each drug
in patients on combination therapy could help
elucidate whether this is the case.
More and detailed studies are needed to confirm
these observations. It would be worthwhile to
further explore whether the use of lower doses of
Yoon 109
currently available oral Hh pathway inhibitors
through combination therapy can help alleviate the
severity of adverse events and make this treatment
more tolerable for patients.
REFERENCES
1. Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Inci-
dence estimate of nonmelanoma skin cancer (keratinocyte
carcinomas) in the U.S. population, 2012. JAMA Dermatol.
2015;151:1081-1086.
2. Gorlin R. Nevoid basal cell carcinoma syndrome. Dermatol Clin.
1995;13:113-125.
3. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of
vismodegib in advanced basal-cell carcinoma. N Engl J Med.
2012;366:2171-2179.
4. Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety
and efficacy of vismodegib in patients with advanced basal
cell carcinoma: final update of the pivotal ERIVANCE BCC
study. BMC Cancer. 2017;17:332.
5. Kim J, Tang JY, Gong R, et al. Itraconazole, a commonly used
antifungal that inhibits Hedgehog pathway activity and cancer
growth. Cancer Cell. 2010;17:388-399.
6. Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory
phase II trial of oral itraconazole for the treatment of basal cell
carcinoma. J Clin Oncol. 2014;32:745-751.
7. Yoon J, Apicelli AJ, Pavlopoulos TV. Intracranial regression of
an advanced basal cell carcinoma using sonidegib and
itraconazole after failure with vismodegib. JAAD Case Rep.
2018;4:10-12.
8. Jager T, Ocker M, Kiesslich T, Neureiter E, Neureiter D.
Thoughts on investigational hedgehog pathway inhibitors
for the treatment of cancer. Expert Opin Investig Drugs. 2017;
26:133-136.
9. Kim J, Lee JJ, Kim J, Gardner D, Beachy PA. Arsenic antagonizes
the Hedgehog pathway by preventing ciliary accumulation
and reducing stability of the Gli2 transcriptional effector. Proc
Natl Acad Sci U S A. 2010;107:13432-13437.
10. Liu M, Liang G, Zheng H, et al. Triazoles bind the C-terminal
domain of SMO: illustration by docking and molecular
dynamics simulations the binding between SMO and triazoles.
Life Sci. 2019;217:222-228.
11. Lorusso PM, Jimeno A, Dy G, et al. Pharmacokinetic
dose-scheduling study of Hedgehog pathway inhibitor
vismodegib (GDC-0449) in patients with locally advanced or
metastatic solid tumors. Clin Cancer Res. 2011;17:5774-5782.
12. Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE.
Role of itraconazole metabolites in CYP3A4 inhibition. Drug
Metab Dispos. 2004;32:1121-1131.